Brain-targeted multifunctional micelles delivering Oridonin and Phillyrin for synergistic therapy of Alzheimer's disease

There is currently a shortage of effective therapeutic drugs for Alzheimer's disease (AD), which is an irreversible neurodegenerative condition. The development of AD is largely influenced by oxidative stress and inflammatory response, which are mediated by glial cells. This condition is further aggravated by abnormal deposition of Aβ and diseased neurons, ultimately worsening the symptoms of AD. In addition, the blocked drug penetration by the blood-brain barrier (BBB) increases the difficulty of AD treatment. Oridonin and Phillyrin have anti-inflammatory, antioxidant, Aβ clearance, and neuroprotective effects. However, their clinical application is limited owing to their difficulty in crossing BBB, poor solubility, and low bioavailability. Therefore, we established ApoE-modified Oridonin and Phillyrin nano-micelles (ApoE-Ori/Phi-Ms), which can pass BBB under the guidance of brain-targeting peptide ApoE, elevate the effective concentration of drug in the brain, and improve the therapeutic effect. The experimental results showed that ApoE-Ori/Phi-Ms had good stability, high drug encapsulation rate, increased concentration in brain tissue, and increased uptake of drugs by nerve cells. In addition, we also found that ApoE-Ori/Phi-Ms improved the cognitive ability of AD mice, alleviated Aβ deposition, neuroinflammation, and oxidative stress, inhibited abnormal activation of astrocytes and microglia, and saved neuronal apoptosis, supplying a promising novel method for the treatment of AD.